This project's long-term goals are to understand mechanisms of chronic inflammatory diseases. Infections initiate or perpetuate many chronic inflammatory diseases. Trypanosoma cruzi chronically infects mice and is an excellent system to investigate mechanisms of infection-induced chronic inflammation. Natural killer T (NKT) cells appear to function as sentinels that inhibit unwanted responses, but when infections occur they can rapidly respond by initiating protective responses. NKT cells are highly sensitive to activation-induced cell death, and their repeated stimulation leads to death or altered Th cytokine production. Many chronic inflammatory and autoimmune diseases are associated with NKT cell populations that are diminished or have altered Th cytokine production. The effect of chronic stimulation or chronic infection on NKT cells is unknown. A candidate antigen of NKT cells, glycophosphoinositol (GPI), is abundantly expressed by T. cruzi. During T. cruzi infection the function of NKT cells in the protective and chronic inflammatory responses have not been examined. This application's specific aims are to determine during T. cruzi infection the function of NKT cells in: the protective immune response; the regulation of a major MHCII CD4 IFNy response; and the chronic inflammatory response. These responses will be analyzed in wild type mice, NKT cell-deficient mice, and NKT cell-deficient mice adoptively transferred with wild type NKT cells or NKT cells lacking effector functions using cellular immunological and histological techniques. Completion of these aims will provide important insights into NKT cell functions during protective and pathologic immune responses.